Ethanol, while at best a weak carcinogen in animal models, increases human risk of cancer at several sites. Elucidation of the mechanism by which it does so would not only illuminate this particular public health issue but also provide insight into the more general question of the impact of interaction between environmental chemicals on cancer risk. Current efforts focus on the effect of ethanol on carcinogen metabolism and clearance in mice. In collaboration with Dr. P.G. Forkert, cytochrome P450IIE1, which activates environmental nitrosamines such as N-nitrosodimethylamine (NDMA), was found to be induced 2- to 7-fold by ethanol in drinking water or liquid diet, as indicated by enzyme assay and Western immunoblotting with a specific monoclonal antibody. Immunohistochemical staining showed uniform staining in centrilobular hepatocytes. Ethanol competitively inhibits, as well as induces, P450 activity toward NDMA, and this was investigated systematically in a toxicokinetic study. Doses of 10-20% ethanol given i.g. before i.v. doses of 1-10 mg/kg NDMA had large negative effects on clearance parameters, up to 25-fold. Even more striking inhibition was seen with oral coadministration, up to 250-fold. Finally, ethanol in the drinking water was found to increase a UDP-glucuronosyltransferase participating in clearance of polycyclic aromatic hydrocarbons.